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WO2006138549A1 - Composes tricycliques utiles comme inhibiteurs de la serotonine et comme agonistes et antagonistes de 5-ht1a - Google Patents

Composes tricycliques utiles comme inhibiteurs de la serotonine et comme agonistes et antagonistes de 5-ht1a Download PDF

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WO2006138549A1
WO2006138549A1 PCT/US2006/023467 US2006023467W WO2006138549A1 WO 2006138549 A1 WO2006138549 A1 WO 2006138549A1 US 2006023467 W US2006023467 W US 2006023467W WO 2006138549 A1 WO2006138549 A1 WO 2006138549A1
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formula
compound
amino
fluoro
indol
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Sivaramakrishnan P. Ramamoorthy
Zhonggi Shen
Boyd L. Harrison
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Wyeth LLC
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Wyeth LLC
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Priority to JP2008517136A priority Critical patent/JP2008543867A/ja
Priority to AU2006259294A priority patent/AU2006259294A1/en
Priority to BRPI0611948-4A priority patent/BRPI0611948A2/pt
Priority to EP06773337A priority patent/EP1893617A1/fr
Priority to MX2007015772A priority patent/MX2007015772A/es
Priority to CA002612109A priority patent/CA2612109A1/fr
Publication of WO2006138549A1 publication Critical patent/WO2006138549A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel 3-amino chroman and 2-amino tetralin derivatives, and in particular, to their use as both serotonin reuptake inhibitors and as 5-HT 1A receptor agonists or antagonists, and to their related use for, inter alia, the treatment and/or prevention of depression and other conditions related to or affected by the reuptake of serotonin and the 5-HT 1A receptor.
  • Major depressive disorder affects an estimated 340 million people worldwide. Depression is the most frequently diagnosed psychiatric disorder and, according to the World Health Organization, is the fourth greatest public health problem. If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some cases, leading to suicide. Symptoms of the disorder include feelings of sadness or emptiness, lack of interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate guilt. In addition to the personal costs of depression, the disorder also has been estimated to result in more than $40 billion in annual costs in the United States alone, due to premature death, lost productivity, and absenteeism.
  • SSRIs serotonin reuptake inhibitors
  • TCAs tricyclic antidepressants
  • SSRIs are believed to work by blocking the neuronal reuptake of serotonin, increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.
  • a single dose of a SSRI can inhibit the neuronal serotonin transporter, and thus would be expected to increase synaptic serotonin, clinical improvement has generally been observed only after long-term treatment. It has been suggested that the delay in onset of antidepressant action of the SSRIs is the result of an increase in serotonin levels in the vicinity of the serotonergic cell bodies.
  • This excess serotonin is believed to activate somatodendritic autoreceptors, i.e., 5-HT 1A receptors, reduce cell firing activity and, in turn, decrease serotonin release in major forebrain areas.
  • This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants acutely.
  • the somatodendritic autoreceptors become desensitized, allowing the full effect of the SSRIs to be expressed in the forebrain. This time period has been found to correspond to the latency for the onset of antidepressant activity [Perez, V., et al, The Lancet, 1997, 349: 1594-1597].
  • a 5-HT 1A agonist or partial agonist acts directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the latency period for the SSRI effect.
  • the 5-HT 1A partial agonists buspirone and gepirone [Feiger, A., Psychopharmacol. Bull, 1996, 32(4): 659-665; Wilcox, C, Psychopharmacol. Bull, 1996, 32(93): 335-342]
  • the 5-HT 1A agonist, flesinoxan [Grof, P., International Clinical Psychopharmacology, 1993, 8(3): 167-172] have shown efficacy in clinical trials for the treatment of depression.
  • This invention relates to 3-amino chroman and 2-amino tetralin derivatives, and in particular, to methods of their use in the treatment and/or prevention of serotonin-related disorders, such as depression (including, but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with or without hyperactivity), obsessive- compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease, and related illnesses.
  • depression including, but not limited to major depressive disorder, childhood depression and dysthymia
  • anxiety anxiety
  • panic disorder posttraumatic stress disorder
  • premenstrual dysphoric disorder also known as premenstrual syndrome
  • attention deficit disorder with
  • Preferred compounds have the ability to bind 5-HT 1A receptors, act as agonists, partial agonists or antagonists at the 5- HT 1 A receptors, and act as serotonin reuptake inhibitors.
  • the present invention provides 3-amino chroman and 2- amino tetralin derivatives of Formula (I):
  • R 3 is a hydrogen, hydroxyl, halogen, -(C 1 -C 3 )-alkyl, -O-(Ci-C 3 )-alkyl, -
  • R 4 and R 5 are each independently hydrogen, hydroxyl, linear or branched -
  • R 6 is hydrogen, a linear or branched -(Ci-C 6 )-alkyl or a linear or branched
  • X and Y are each independently -CR 18 R 19 -, -O-, -NR 18 - or -S-;
  • Z 1 is carbon or nitrogen
  • Z 2 is carbon and Z 3 is carbon, nitrogen, oxygen or sulfur
  • at least one of Z 1 and Z 3 is not carbon, wherein a double bond is optionally present between Z 1 and Z 2 , wherein A 1 is attached to R 7 through Z 1 , Z 2 or Z 3 except when Z 3 is oxygen, and further wherein when R 7 is linked to Z 3 , then Z 3 is nitrogen;
  • R 12 and R 13 are each independently hydrogen or a linear or branched -(C 1 -
  • R 12 and R 13 may be attached at any of Z 1 , Z 2 or Z 3 , and further wherein R 13 is optionally present at Z 1 or Z 2 when Z 3 is oxygen;
  • Ri 4 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently hydrogen, hydroxyl, halogen, a linear or branched (Ci-C 6 )-alkyl or a linear or branched (C 2 -C 6 )-alkenyl; R2 0 is a hydrogen, a linear or branched (Ci-C 6 )-alkyl or a (C 3 -C 7 )-cycloalkyl; and fhe dotted lines represent optional double bonds.
  • A is A 2
  • R 15 , R 16 , R 17 , R 18 and R 19 are each independently hydrogen, hydroxyl, halogen, a linear or branched (Ci-C 6 )-alkyl or a linear or branched (C 2 -C 6 )-alkenyl
  • R2 0 is a hydrogen, a linear or branched (Ci-C 6 )-alkyl or a (C 3 -C 7
  • Y is -NH- or -O-.
  • R 7 is linked at Zi
  • Z 3 is -N-
  • R 13 is hydrogen or -CH3
  • a double bond is present between Zi and Z 2 .
  • A is A 1
  • Z 1 is carbon
  • Z 3 is -O-
  • R 13 is not present, and a double bond is present between Z 1 and Z 2 .
  • R 6 is selected from: [0023] -(CH 2 ) m -B, m is 0 or 1 , and B is a C 3 -C 6 -cycloalkyl, a linear C 2 -C 4 -alkyl, or a branched C 3 -C 5 -alkyl,
  • ⁇ (CH 2 ) m -B, m is 0 or 1
  • B is an aromatic (C 5 ⁇ C 7 )-carbocyclic ring, wherein one to two ring atoms may optionally be replaced by an oxygen
  • -(CH 2 ) m -B, m is 2, 3 or 4
  • B is a phenyl fused to a saturated, partially saturated or aromatic (C 5 -C 7 )-carbocyclic ring, wherein the phenyl or carbocyclic ring is optionally substituted by one to two halogen atoms, further wherein one to two ring atoms of the (C 5 -C 7 )-carbocyclic ring may optionally be replaced by a nitrogen or oxygen atom.
  • A is
  • A is
  • R 12 is a linear -(C 1 -C 6 )-alkyl, preferably methyl or ethyl.
  • R 12 is a linear -(C 1 -C 6 )-alkyl, preferably methyl or ethyl.
  • At least one of R 5 , R 8 , R 9 , R 1O and R 11 is fluorine.
  • R 8 , R 9 , and R 11 are hydrogen and R 10 is fluorine.
  • R 3 is preferably -CH 3 or hydrogen, and more preferably -CH 3 in particular embodiments.
  • R 4 or R 5 is -C)-CH 2 or -NO 2 .
  • R 4 is preferably hydrogen.
  • R5 preferably being -OR 14 , halogen or hydrogen and in particular, R 5 being -OCH 3 .
  • R 7 is preferably a linear -(Ci-C 4 )-alkylene- or -(CH 2 ) P -(C 3 -C 6 )- cycloalkyl-(CH 2 ) q -. In further preferred embodiments, R 7 is
  • the present invention provides compounds of Formula (Ia):
  • R 3 , R 4 , Rs 1 R 6 , R 7 , R 8 , Rg, R 10 and R 11 are as previously defined, or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof.
  • the present invention is directed to compounds of Formula (Ib)
  • R 3 , R 4 , R 5, R 6> R 7 are as previously defined, or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof.
  • R 8; R 9 , R 10 and R 11 are as previously defined, or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof.
  • the compounds are of Formula (Ic)
  • R 3 , R 41 R 5 , R 61 R 7> R 81 R 9j R 10 , R 11 and R 12 are as previously defined, or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof.
  • Particular embodiments include at least one of the following: R 3 , R 4, R 8, R 9 and R 11 are hydrogen; R 5 is -OCH 3 or fluorine; R 6 is -(CH 2 ) m -B, with -B being a -(C 3 -C 5 )-cycloalkyl (in particular where m is 1 and B is a C 4 -cycloalkyl ring, i.e., cyclobutyl ring); R 7 is -(CH 2 ) p -(C 3 -C 6 )-cycloalkyl-(CH 2 ) q - (particularly where p is 0 and q is 1 or p is 1 and q is 0, and the cycloalkyl is a
  • the present invention is directed to the compounds or a prodrug, stereoisomer or pharmaceutically-acceptable salt thereof of the compound of Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) and one or more pharmaceutically acceptable carriers.
  • the compounds or pharmaceutically acceptable salts of the compounds of the Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) are useful as serotonin reuptake inhibitors.
  • the compounds or pharmaceutically acceptable salts of the compounds of the Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) are useful as agonists and/or antagonists of 5-HT 1A receptors.
  • the present invention also provides methods of treating and/or preventing a serotonin-related disorder in a patient suspected of suffering from a serotonin-related disorder, comprising the step of administering to the patient a therapeutically effective amount of a compound of Formula (I) or Formula (Ia) or Formula (Ib).
  • the present invention provides methods for treating and/or preventing depression (including, but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with or without hyperactivity), obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease, and related illnesses.
  • depression including, but not limited to major depressive disorder, childhood depression and dysthymia
  • anxiety anxiety
  • panic disorder post-traumatic stress disorder
  • premenstrual dysphoric disorder also known as premenstrual syndrome
  • attention deficit disorder with or without hyperactivity
  • obsessive compulsive disorder social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervos
  • the present invention is directed to methods of inhibiting the reuptake of serotonin in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of Formula (I) or Formula (Ia) or Formula (Ib).
  • the present invention is also directed to a method of agonizing and/or antagonizing 5-HT 1A receptors in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of Formula (I) or Formula (Ia) or Formula (Ib).
  • the present invention further relates to a method of making a compound of the invention of Formula (I), wherein said method comprises [0046] (a) nitrating a compound of formula (II)
  • R 2 is the corresponding aldehyde of R 7 under conditions sufficient to produce a compound of formula
  • the method further comprises the step of alkylating the compound of formula (II) with an alkyl halide under conditions sufficient to produce a compound of formula (Ha)
  • step (b) wherein R 3 is a -(Ci-C 3 )-alkyl.
  • the instant invention further provides a method of making a compound of formula (XII)
  • the present invention further includes a method whereby the compound of formula (XII) is subject to a propargylating reaction under conditions sufficient to produce a compound of formula (XIIa)
  • R 3 is hydrogen or a -(C 1 -C 3 ) alkyl.
  • R 3 is an alkyl, for example, the compound is alkylated by reaction with an alkyl halide under conditions sufficient to substitute R 3 for H. Other methods known in the art may be used to substitute additional R 3 groups.
  • the invention provides a method of making a compound of
  • R 6 is a -(C 1 -C 3 )-alkyl, or is optionally subjected to a reductive animation by reacting with a compound of formula R 6 CHO to produce a compound of formula (XVII)
  • the invention further provides a method of making a compound of
  • the present invention further provides a method of making a compound of formula (lib)
  • R 3 is hydrogen or a -(C 1 -C 3 ) alkyl.
  • R 3 to be an alkyl, for example, the compound may be alkylated by reaction with an alkyl halide under conditions sufficient to substitute R 3 for H. Other methods known in the art may be used to substitute additional R 3 groups.
  • the invention further provides a method, which method is further comprising
  • a compound of formula XXXI may optionally be substituted with R 3 as defined in Formula I by methods known by those skilled in the art. [0091] It should be understood that these preferred processes may be modified in accordance with ordinary skill in the art.
  • (C 1 -C 6 )-alkyl refers to a linear or branched, saturated hydrocarbon having from 1 to 6 carbon atoms.
  • Representative (Ci-C 6 )-alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, and neohexyl.
  • the (Ci-C 6 )-alkyl group is substituted with one or more of the following groups: halogen, -N 3 , -NO 2 , -CN, -OR', -SR',
  • (C 2 -C 6 )-alkenyl refers to a linear or branched hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon double bond. In one embodiment, the (C 2 -C 6 )-alkenyl has one or two double bonds.
  • the (C 2 -C 6 )-alkenyl moiety may exist in the E or Z conformation and the compounds of the present invention include both conformations.
  • the (C 2 -C 6 )-alkenyl group is substituted with one or more of the following groups: halogen, -N 3 , -NO 2 , -CN, - OR', -SR', -SO 2 R', -SO 2 N(R') 2 , -N(R') 2 , -COR', -CO 2 R', -NR 5 CO 2 R', -NR'COR', - NR' CONR', or -CON(R' ) 2 , wherein each R' is independently hydrogen or unsubstituted (Ci-C 6 )-alkyl.
  • (C 2 -C 6 )-alkynyl refers to a linear or branched hydrocarbon having from 2 to 6 carbon atoms and having at least one carbon-carbon triple bond.
  • the (C 2 -C 6 )-alkynyl group is substituted with one or more of the following groups: halogen, -N 3 , -NO 2 , -CN, -OR', -SR', -SO 2 R', -SO 2 N(R') 2 , -N(R') 2 , -COR', -CO 2 R', -NR 5 CO 2 R', -NR'COR 5 , -NR 5 CONR 5 , or -CON(R') 2 , wherein each R 5 is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl.
  • administer refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to an animal, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the animal, which can form an equivalent amount of active compound within the animal's body.
  • animal as used herein includes, without limitation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus. In one embodiment, the animal is a mammal. In another embodiment, the animal is a human.
  • aryl refers to an aromatic species containing 1 to 3 aromatic rings, either fused or linked.
  • the aryl group is substituted with one or more of the following groups: VH, -V-halogen, -V-N 3 , -V-NO 2 , - V-CN, -V-OR', -V-SR', -V-SO 2 R 5 , -V-SO 2 N(R' ) 2 , -V-N(R 5 ) 2 , -V-COR' , -V-CO 2 R' , -V-NR' CO 2 R' , -V- NR' COR',
  • cyclic group as used herein includes a cycloalkyl group and a heterocyclic group. Any suitable ring position of the cyclic group may be covalently linked to the defined chemical structure.
  • the cyclic group is substituted with one or more of the following groups: VH, -V-halogen, -V-N 3 , -V-NO 2 , - V-CN, -V-OR' , -V-SR' , -V-SO 2 R' , -V-SO 2 N(R' ) 2 , -V-N(R' ) 2 , -V-COR' , -V-CO 2 R' , -V- NR 1 CO 2 R', -V-NR'COR', -V-NR 1 CONR', or -V-CON(R' ) 2 , wherein each R' is independently hydrogen or unsubstituted (Ci-C 6 )-alkyl; and wherein each V is independently a bond or (CrC 6 )-alkyl.
  • cycloalkyl group refers to a three- to seven- membered saturated or partially unsaturated carbon ring. Any suitable ring position of the cycloalkyl group may be covalently linked to the defined chemical structure.
  • exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • the cycloalkyl group is substituted with one or more of the following groups: VH, -V-halogen, -V-N 3 , -V-NO 2 , -V-CN, -V-OR', -V-SR', -V-SO 2 R', -V-SO 2 N(R') 2 , -V- N(R') 2 ,
  • the term "effective amount” as used herein refers to an amount of a compound or pharmaceutically acceptable salt of a compound that, when administered to an animal, is effective to prevent, to at least partially ameliorate, or to cure, a condition from which the animal suffers or is suspected to suffer.
  • carrier shall encompass carriers, excipients, and diluents.
  • prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula (I), (Ia) or (Ib).
  • halogen refers to fluorine, chlorine, bromine, and iodine.
  • heterocyclic group refers to a three- to seven- membered saturated, partially saturated, or unsaturated cycloalkyl group in which one to four of the ring carbon atoms have been independently replaced with a N, O, or S atom. Any suitable ring position of the heterocyclic group may be covalently linked to the defined chemical structure.
  • heterocyclic groups include, but are not limited to, azepanyl, azetidinyl, aziridinyl, furanyl, furazanyl, homopiperazinyl, imidazolidinyl, imidazolinyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyr
  • the heterocyclic group is substituted with one or more of the following groups: VH, -V-halogen, -V-N3, -V-N02, -V-CN, -V-OR', -V-SR', -V-SO2R', -V-SO2N(R')2, -V-N(R')2, -V-COR', -V-CO2R', -V-NR'C02R ⁇ -V-NR'COR', -V- NR' CONR', or -V-CON(R' )2, wherein each R' is independently hydrogen or unsubstituted (Cl-C6)-alkyl; and wherein each V is independently a bond or (C1-C6)- alkyl.
  • the term "isolated and purified” as used herein refers to a component separated from other components of a reaction mixture or a natural source.
  • the isolate contains at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or pharmaceutically acceptable salt of the compound by weight of the isolate.
  • pharmaceutically acceptable salt refers to a salt of an acid and a basic nitrogen atom of a compound of the present invention.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamo
  • phenyl refers to a substituted or unsubstituted phenyl group.
  • the phenyl group is substituted with one or more of the following groups: VH, -V-halogen, -V-N 3 , -V-NO 2 , -V-CN, -V-OR', -V-SR', -V- SO 2 R', -V-SO 2 N(R') 2 ,
  • each R' is independently hydrogen or unsubstituted (C 1 -C 6 )-alkyl; and wherein each V is independently a bond or (CrC 6 )-alkyl.
  • the compound that is substantially free of its corresponding opposite entantiomer contains no more than about 5%, no more than about 1%, no more than about 0.5%, or no more than about 0.1% by weight of its corresponding opposite enantiomer.
  • An enantiomer that is substantially free of its corresponding opposite enantiomer includes a compound that has been isolated and purified or has been prepared substantially free of its corresponding opposite enantiomer.
  • tautomer refers to compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 69-74 (1992). (b) Compounds and Pharmaceutically Acceptable Salts of Compounds of the
  • the present invention is directed to compounds of the
  • R 3 is a hydrogen, hydroxyl, halogen, -(Q-C ⁇ -alkyl, -CHCi-C 3 )-a]kyl, - (C 3 -C 6 )-cycloalkyl, -SO 2 R 20 , or -COR 20 , wherein -(C r C 3 )-alkyl, -O-(C r C 3 )-alkyl, or -(C 3 -C 6 )-cycloalkyl are optionally branched.
  • R 4 and R 5 are each independently hydrogen, hydroxyl, linear or branched -
  • (Ci-C 6 )-alkyl linear or branched -(C 2 -C 6 )-alkenyl, halogen, -COR 14 , -OR 14 , -SR 14 , -SO 2 NR 14 R 15 , -NO 2 , -CONR 14 R 15 or -(C 3 -C 6 )-cycloalkyl, which optionally contains a nitrogen, oxygen or sulfur atom;
  • R 6 is hydrogen, a linear or branched -(C 1 -C 6 )-alkyl or a linear or branched
  • B is a (C 3 -Cs)- cycloalkyl, a saturated, partially saturated or aromatic (C 5 -C 7 )-carbocyclic ring or a phenyl fused to a saturated, partially saturated or aromatic (C 5 -C 7 )-carbocyclic ring, wherein the cycloalkyl, phenyl or carbocyclic ring is optionally substituted by one to two substituents per ring, wherein said substituents are independently selected from the group consisting of halogen, cyano, -(CrC 6 )-alkyl, -(C 2 -C 6 )-alkenyl,
  • R 7 is selected from a linear or branched -(Q-C ⁇ -alkylene-, linear or branched -(C 2 -C 6 )-alkenylene- or -(CH 2 )p-(C 3 -C 6 )-cycloalkyl-(CH 2 ) q -, each of which is optionally substituted with a halogen or hydroxyl, wherein one or two ring atoms of the cycloalkyl may optionally replaced by a nitrogen, sulfur or oxygen atom, and p and q are each independently 0, 1 or 2;
  • Q is selected from -(Q-C ⁇ -alkylene-, -O-(C r C 2 )-alkylene-, -(C 2 -C 3 )- alkenylene-, or -O-(C 2 )-alkenylene-, wherein the alkylene or alkenylene is optionally substituted with a -(d-C 3 )-alkyl or a halogen, and wherein for -O-(CrC 2 )-alkylene- or -
  • Z 1 is carbon or nitrogen
  • Z 2 is carbon and Z 3 is carbon, nitrogen, oxygen or sulfur
  • at least one of Z 1 and Z 3 is not carbon, wherein a double bond is optionally present between Z 1 and Z 2 , wherein A 1 is attached to R 7 through Z 1 , Z 2 or Z 3 , except when Z 3 is oxygen, and further wherein when R 7 is linked to Z 3 , then Z 3 is nitrogen;
  • R 12 and R 13 are each independently hydrogen or a linear or branched -(C 1 -
  • R 12 and R 13 may be attached at any of Z 1 , Z 2 or Z 3 , and further wherein R 13 is optionally present at Z 1 or Z 2 when Z 3 is oxygen;
  • R 14 , R 15 , R 16 , R 17 , R 18 and R 19 are each independently hydrogen, hydroxyl, halogen, a linear or branched (C 1 -C 6 )-alkyl or a linear or branched (C 2 -C 6 )-alkenyl;
  • R 20 is a hydrogen, a linear or branched (Ci-C 6 )-alkyl or a (C 3 -C 7 )-cycloalkyl; and the dotted lines represent optional double bonds.
  • This invention relates to both the R and S stereoisomers of the 3-amino- chroman or 2-amino-tetralin derivatives, as well as to racemic mixtures of the R and S stereoisomers.
  • the name of the product of this invention where the absolute configuration of the 3-amino-chromans or 2-amino tetralins is not indicated, is intended to embrace the individual R and S enantiomers, as well as racemic mixtures.
  • This invention also relates to both the R and S stereoisomers at the carbon alpha or beta from the basic nitrogen.
  • the name of the product of this invention where the absolute configuration at the above two positions is not indicated, is intended to embrace the individual R and S enantiomers.
  • a stereoisomer is preferred, it may in some embodiments be provided substantially free of the corresponding enantiomer.
  • an enantiomer substantially free of the corresponding enantiomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding enantiomer.
  • substantially free means that the compound is made up of a significantly greater proportion of one stereoisomer, preferably less than about 50%, more preferably less than about 75%, and even more preferably less than about 90%.
  • the preferred stereoisomer was isolated from racemic mixtures by high performance liquid chromatography (HPI C) using a chiral column.
  • HPI C high performance liquid chromatography
  • the compound of general Formula (I) and compounds of structures (Ia) and (Ib) may be prepared by conventional synthetic techniques.
  • suitable aprotic polar solvents include, but are not limited to, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, acetone and ethanol.
  • suitable acid binding agents include, but are not limited to, organic tertiary bases, such as, for example, triethylamine, triethanolamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and diisopropylethylamine (DIPEA); and alkaline metal carbonates, such as, for example, potassium carbonate and sodium carbonates.
  • Suitable reducing agents include, but are not limited to, sodium cyanoborohydri.de and sodium triacetoxyborohydride.
  • a suitably substituted ortho-bromobenzoic acid is protected as the methyl ester by alkylation with methyl iodide in the presence of a base such as DBU in a polar solvent like DMF.
  • the bromo functionality is replaced by a methyl on treatment with dimethylzinc in the presence of a nickel catalyst.
  • Benzylic bromination under standard conditions followed by heating with ammonia yields the lactam.
  • Deprotection of the methyl ether under standard conditions with a Lewis acid such as BBr 3 yields the phenol.
  • the phenol is propargylated under standard conditions with propargyl bromide and a base such as potassium carbonate.
  • the propargyl ether is then subject to heating in N,N-diethylaniline to yield the dihydropyran.
  • This amine is then subject to reductive amination under standard conditions with a appropriately substituted aldehyde in the presence of sodiumcyanoborohydride and acetic acid in a polar solvent such as methanol.
  • a polar solvent such as methanol.
  • This secondary amine is then subject to one of two reaction conditions depending on the choice of R 6 that is required.
  • R 6 is a methyl
  • the secondary amine is alkylated with trimethyloxonium tetrafluoroborate in the presence of a base such as Hunig's base (diisopropylethylamine).
  • Hunig's base diisopropylethylamine
  • a second reductive amination gives additional compounds of this invention where R 6 is as defined in the generic structure.
  • the preparation of the bicyclic aldehyde employed in this synthesis was previously disclosed in U.S. Application No. 10/898,866, filed July 26, 2004, which is hereby incorporated by reference in its entirety.
  • Scheme 4 describes the preparation of compounds in this invention wherein the nitrogen on the lactam moiety is alkylated.
  • alkylation with an alkyl halide such as methyl iodide (MeI) after treatment with a base such as sodium hydride (NaH) yields the alkylated lactam.
  • a base such as sodium hydride (NaH)
  • Scheme 5 describes the synthesis of compounds in this invention that contain a six-membered lactam ring.
  • An appropriately substituted indanone is subject to a modified Schmidt rearrangement with sodium azide and methanesulfonic acid. This reaction yields a mixture of regioisomeric lactams from which the desired lactam is separated by standard column chromatography. This lactam is then subject to the same sequence of steps described in schemes 1 and 2 to yield the desired targets.
  • Scheme 6 describes the preparation of intermediates that contain a fluorine substituent para to the carbonyl group of the lactam.
  • An appropriately substituted bromobenzene is subject to a Heck reaction with methyl acrylate in the presence of a catalytic amount of palladium acetate (Pd(OAc) 2 ) and tri-o-tolylphosphine (P(o-tol) 3 ).
  • Pd(OAc) 2 palladium acetate
  • P(o-tol) 3 tri-o-tolylphosphine
  • the unsaturated methyl ester is reduced to the saturated methyl ester under standard hydrogenation conditions using catalytic palladium on carbon under an atmosphere of hydrogen.
  • the methyl ester is then hydrolysed under standard conditions to give the carboxylic acid.
  • This carboxylic acid is then cyclized by heating in the presence of a Lewis acid such as aluminum trichloride (AICI 3 ) to give the indanone.
  • AICI 3 aluminum trichloride
  • the indanone is then subject to a modified Schmidt rearrangement as described in scheme 5 to yield a mixture of regioisomeric lactams.
  • the desired lactam (as shown) is then isolated by column chromatography.
  • “effective dosage” as used herein refer to the amount of a compound of Formula (I), (Ia) and (Ib) that, when administered to a patient, is effective to at least partially ameliorate a condition form which the patient is suspected to suffer.
  • Such conditions include, but are not limited to, depression (including, but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with or without hyperactivity), obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease, and related illnesses.
  • Compounds of Formula (I) have been found to act as serotonin reuptake inhibitors and to have an affinity for the 5-HT 1A reuptake transporter. They are therefore useful in the treatment of diseases affected by disorders of the serotonin affected neurological systems, including, but not limited to, depression (including, but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with or without hyperactivity), obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease, and related illnesses.
  • depression including, but not limited to major depressive disorder, childhood depression and dysthymia
  • anxiety anxiety
  • panic disorder post-traumatic stress disorder
  • compositions comprising at least one compound of Formula (I); and optionally one or more pharmaceutically acceptable carrier, excipient, or diluents.
  • the compounds or pharmaceutically acceptable salts of the compounds can be administered neat or as a component of a composition that comprises a physiologically acceptable carrier or vehicle.
  • a composition of the invention can be prepared using a method comprising admixing the compound or a pharmaceutically acceptable salt of the compound and a physiologically acceptable carrier, excipient, or diluent. Admixing can be accomplished using methods well known for admixing a compound or a pharmaceutically acceptable salt of the compound and a physiologically acceptable carrier, exipient, or diluent.
  • compositions comprising compounds or pharmaceutically acceptable salts of the compounds of the invention can be administered orally.
  • the compounds or pharmaceutically acceptable salts of compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, vaginal, and intestinal mucosa, etc.) and can be administered together with another therapeutic agent. Administration can be systemic or local.
  • Various known delivery systems including encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal , transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin.
  • administration will result of release of the compound or a pharmaceutically acceptable salt of the compound into the bloodstream.
  • the mode of administration is left to the discretion of the practitioner.
  • the compound or a pharmaceutically acceptable salt of the compound is administered orally.
  • the compound or a pharmaceutically acceptable salt of the compound is administered intravenously.
  • the compound or a pharmaceutically acceptable salt of the compound into the central nervous system, circulatory system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and by injection adjacent to the peripheral nerve.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the compound or a pharmaceutically acceptable salt of the compound can be formulated as a suppository, with traditional binders and excipients such as triglycerides.
  • the compound or a pharmaceutically acceptable salt of the compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990) and Treat et al, Liposomes in the Therapy of Infectious Disease and Cancer 317-327 and 353-365 (1989)).
  • the compound or a pharmaceutically acceptable salt of the compound can be delivered in a controlled-release system or sustained-release system (see, e.g., Goodson, in Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled or sustained-release systems discussed in the review by Langer, Science 249:1527-1533 (1990) can be used.
  • a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); and Saudek et al., N. Engl. J Med. 32J,:574 (1989)).
  • polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball eds., 1984); Ranger and Peppas, /. Macromol. ScL Rev. Macromol. Chem.
  • a controlled- or sustained-release system can be placed in proximity of a target of the compound or a pharmaceutically acceptable salt of the compound, e.g., the reproductive organs, thus requiring only a fraction of the systemic dose.
  • compositions can optionally comprise a suitable amount of a physiologically acceptable excipient.
  • physiologically acceptable excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the physiologically acceptable excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the physiologically acceptable excipients are sterile when administered to an animal.
  • the physiologically acceptable excipient should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms.
  • Water is a particularly useful excipient when the compound or a pharmaceutically acceptable salt of the compound is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.
  • Suitable physiologically acceptable excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • compositions can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs.
  • the compound or pharmaceutically acceptable salt of the compound of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives including solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators.
  • liquid carriers for oral and prenteral administration include water (particular containing additives as above, e.g., cellulose derivatives, including sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule.
  • suitable physiologically acceptable excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro, ed., 19th ed. 1995).
  • the compound or a pharmaceutically acceptable salt of the compound is formulated in accordance with routine procedures as a composition adapted for oral administration to humans.
  • compositions for oral delivery can be in the form of tablets, lozenges, buccal forms, troches, aqueous or oily suspensions or solutions, granules, powders, emulsions, capsules, syrups, or elixirs for example.
  • Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • the carrier can be a finely divided solid, which is an admixture with the finely divided compound or pharmaceutically acceptable salt of the compound.
  • the compound or pharmaceutically acceptable salt of the compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets can contain up to about 99% of the compound or pharmaceutically acceptable salt of the compound.
  • Capsules may contain mixtures of the compounds or pharmaceutically acceptable salts of the compounds with inert fillers and/or diluents such as pharmaceutically acceptable starches ⁇ e.g., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (such as crystalline and microcrystalline celluloses), flours, gelatins, gums, etc.
  • inert fillers and/or diluents such as pharmaceutically acceptable starches ⁇ e.g., corn, potato, or tapioca starch
  • sugars such as crystalline and microcrystalline celluloses
  • powdered celluloses such as crystalline and microcrystalline celluloses
  • flours such as crystalline and microcrystalline celluloses
  • gelatins such as crystalline and microcrystalline celluloses
  • Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrroldine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins.
  • pharmaceutically acceptable diluents including
  • Surface modifying agents include nonionic and anionic surface modifying agents.
  • Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • compositions when in a tablet or pill form, can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound or a pharmaceutically acceptable salt of the compound are also suitable for orally administered compositions.
  • fluid from the environment surrounding the capsule can be imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment the excipients are of pharmaceutical grade.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • a local anesthetic such as lignocaine to lessen pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent.
  • the compound or a pharmaceutically acceptable salt of the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • the compound or pharmaceutically acceptable salt of the compound can be administered transdermally thorugh the use of a transdermal patch.
  • Transdermal administrations include administrations across the surface of the body and the inner linings of the bodily passages including epithelial and mucosal tissues.
  • Such administrations can be carried out using the present compounds or pharmaceutically acceptable salts of the compounds, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal or vaginal).
  • Transdermal administration can be accomplished through the use of a transdermal patch containing the compound or pharmaceutically acceptable salt of the compound and a carrier that is inert to the compound or pharmaceutically acceptable salt of the compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams or ointments, pastes, gels, or occlusive devices.
  • the creams or ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to release the compound or pharmaceutically acceptable salt of the compund into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound or pharmaceutically acceptable salt of the compound with or without a carrier, or a matrix containing the active ingredient.
  • the compounds or pharmaceutically acceptable salts of the compounds of the invention may be administered rectally or vaginally in the form of a conventional suppository.
  • Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin.
  • Water-soluble suppository bases such as polyethylene glycols of various molecular weights, may also be used.
  • the compound or a pharmaceutically acceptable salt of the compound can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art.
  • dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention.
  • a controlled- or sustained-release composition comprises a minimal amount of the compound or a pharmaceutically acceptable salt of the compound to treat or prevent a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor in a minimal amount of time.
  • controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased compliance by the animal being treated, hi addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compound or a pharmaceutically acceptable salt of the compound, and can thus reduce the occurrence of adverse side effects.
  • Controlled- or sustained-release compositions can initially release an amount of the compound or a pharmaceutically acceptable salt of the compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the compound or a pharmaceutically acceptable salt of the compound to maintain this level of therapeutic or prophylactic effect over an extended period of time.
  • the compound or a pharmaceutically acceptable salt of the compound can be released from the dosage form at a rate that will replace the amount of the compound or a pharmaceutically acceptable salt of the compound being metabolized and excreted from the body.
  • Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.
  • the present invention is directed to prodrugs of the compounds or pharmaceutically acceptable salts of compounds of the present invention.
  • prodrugs are known in the art, for example as discussed in Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder et al (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Kgrogsgaard-Larsen et al. (ed.); "Design and Application of Prodrugs", Textbook of ' Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard et al, Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard et al., J. Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.), Prodrugs as Novel Drug Deilvery Systems, American Chemical Society (1975).
  • the amount of the compound or a pharmaceutically acceptable salt of the compound that is effective for treating or preventing a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor will vary. In vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner.
  • Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months.
  • the number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner.
  • the effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound or a pharmaceutically acceptable salt of the compound is administered, the effective dosage amounts correspond to the total amount administered.
  • the amount of the compound or a pharmaceutically acceptable salt of the compound that is effective for treating or preventing a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor will typically range from about 0.001 mg/kg to about 250 mg/kg of body weight per day, in one embodiment, from about 1 mg/kg to about 250 mg/kg body weight per day, in another embodiment, from about 1 mg/kg to about 50 mg/kg body weight per day, and in another embodiment, from about 5 mg/kg to about 25 mg/kg of body weight per day.
  • the compounds may be given in a single dose or in two or more divided doses.
  • the pharmaceutical composition is in unit dosage form, e.g., as a tablet, capsule, powder, solution, suspension, emulsion, granule, or suppository.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • the unit dosage form can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • Such unit dosage form may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg.
  • Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention.
  • Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
  • the effective dosage may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated.
  • compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amount".
  • the dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician.
  • the variables involved include the specific condition and the size, age and response pattern of the patient.
  • Effective administration of the compounds of this invention may be given at an oral dose of from about 0.1 mg/day to about 1000 mg/day.
  • administration will be from about 10 mg/day to about 600 mg/day, more preferably, a starting dose is about 5 mg/day with gradual increase in the daily dose to about 150 mg/day, to provide the desired dosage level in the human.
  • Doses may be administered in a single dose or in two or more divided doses. The projected daily dosages are expected to vary with route of administration.
  • the compound or a pharmaceutically acceptable salt of the compound can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy.
  • the present methods for treating or preventing a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor can further comprise administering another therapeutic agent to the animal being administered the compound or a pharmaceutically acceptable salt of the compound. In one embodiment, the other therapeutic agent is administered in an effective amount.
  • Effective amounts of the other therapeutic agents are well known to those skilled in the art. However, it is well within the skilled artisan's purview to determine the other therapeutic agent's optimal effective amount range.
  • the compound or a pharmaceutically acceptable salt of the compound and the other therapeutic agent can act additively or synergistically.
  • the compound or a pharmaceutically acceptable salt of the compound is administered concurrently with another therapeutic agent.
  • a composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound and an effective amount of another therapeutic agent within the same composition can be administered.
  • a composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound and a separate composition comprising an effective amount of another therapeutic agent can be concurrently administered.
  • an effective amount of the compound or a pharmaceutically acceptable salt of the compound is administered prior to or subsequent to administration of an effective amount of another therapeutic agent.
  • the compound or a pharmaceutically acceptable salt of the compound is administered while the other therapeutic agent exerts its therapeutic effect, or the other therapeutic agent is administered while the compound or a pharmaceutically acceptable salt of the compound exerts its preventative or therapeutic effect for treating or preventing a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor.
  • the invention provides a composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.
  • the compounds or pharmaceutically acceptable salts of the compounds of the present invention are useful as serotonin reuptake inhibitors and as 5-HT 1A receptor agonists or antagonists. Accordingly, the compounds and pharmaceutically acceptable salts of the compounds of the present invention are useful for treating a mammal with a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor.
  • the invention provides a method for treating a condition related to or affected by the reuptake of serotonin and the 5-HTI A receptor, comprising administering to a mammal in need thereof a compound or a pharmaceutically acceptable salt of the compound of Formula (I), Formula (Ia) or Formula (Ib) or Formula
  • the condition is depression (including, but not limited to major depressive disorder, childhood depression and dysthymia). In additional embodiments, the condition is anxiety, panic disorder or post-traumatic stress disorder.
  • condition is premenstrual dysphoric disorder
  • condition to be treated or prevented can be attention deficit disorder (with or without hyperactivity).
  • a further embodiment is the treatment or prevention of obsessive compulsive disorder. Additionally, the condition to be treated or prevented is social anxiety disorder or generalized anxiety disorder.
  • the condition to be treated or prevented is obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction or sexual dysfunction.
  • the present invention is directed to a method for modulating the reuptake of serotonin or the activity of a 5-HT 1A receptor, comprising contacting the receptor with an effective amount of a compound or pharmaceutically acceptable salt of the compound of Formula (I) or Formula (Ia).
  • the method further comprises determining the activity of the receptor.
  • the step of determining the activity of the receptor is performed before the step of contacting the receptor with the compound or a pharmaceutically acceptable salt of the compound.
  • the step of determining the activity of the receptor is performed after the step of contacting the receptor with the compound or a pharmaceutically acceptable salt of the compound.
  • the compounds and pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) are also useful in the manufacture of medicaments for treating a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor in a mammal.
  • the invention provides the use of a compound or pharmaceutically acceptable salt of the compound of Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) for the manufacture of a medicament for treating a condition related to or affected by the reuptake of serotonin and the 5-HT 1A receptor.
  • the present invention is directed to the use of a compound or pharmaceutically acceptable salt of the compound of Formula (I) or Formula (Ia) or Formula (Ib) or Formula (Ic) for the manufacture of a medicament for modulating the activity of reuptake of serotonin and of the 5-HTJ A receptor.
  • the medicament is also for determining the activity of the receptor.
  • the present invention further provides a compound of the invention for use as an active therapeutic substance.
  • Compounds of the invention are of particular use in the treatment of diseases affected by disorders of serotonin.
  • the present invention further provides a method for treating depression
  • Example 12 S-Kcyclohexylmethy ⁇ tS-C ⁇ -fluoro-lH-indol-S-y ⁇ propyUaminol-ljSjS ⁇ - tetrahydropyrano[3,2-e]isoindol-l(7H)-one (15) [0205] The title compound (15) was prepared as Example 4. MS (ES) m/z 476.3.
  • the agonist or antagonist activity at 5-HT 1A receptors was established by using two different assays.
  • the 35 S-GTPyS binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol., 1993, 109: 1120) was used to determine the test compound's ability to affect the binding of 35 S-GTPTS to membranes containing cloned human 5-HT 1A receptors.
  • Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8- OH-DPAT.
  • the test compound's maximum stimulatory effect is represented as the E max , while its potency is defined by the EC 50 .
  • the test compound's maximum inhibitory effect is represented as the I max , while its potency is defined by the IC 50 .
  • the second assay measured cAMP accumulation upon binding of the ligand to the 5-HT 1A receptor. Antagonists block the effect of the standard agonist 8-OH-DPAT resulting in an increase in cAMP accumulation while agonists have the reverse effect.
  • the test compound's maximum stimulatory or inhibitory effect is represented as the E max while its potency is defined by either IC 50 for an antagonist or EC 50 for an agonist. [ 3 H]-8-OH-DPAT was used to determine maximum agonist or antagonist response in both functional assays.
  • MATERIALS AND METHODS Stabily transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are scraped off the plate, transfered to centrifuge tubes, and washed twice by centrifugatinn (2000 rpm for 10 min., 4 C) in buffer (50 mM Tris pH 7.5). The resulting pellets are aliquoted and placed at -80 C. On day of assay, the cells are thawed on ice, and resuspended in buffer. The binding assay is performed in a 96 well microliter plate in a total volume of 250 mL.
  • Non-specific binding is determined in the presence of 10 mM 5HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated 6y the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEI. Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1, and 0.01 mM. Subsequently, Kj values are determined for compounds defined to be active. [0293] MEASUREMENTS : Percent Inhibition
  • Example 96 cAMP RIA in CHO Cell Stabily Transfected with the h5HTla Receptor [0294] MATERIALS AND METHODS: Stabily transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells are plated at a density of x 10(6) cells per well in a 24 well plate and incubated for 2 days in a CO2 incubator. On the second day, the media is replaced with 0.5 ml treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 uM pargyline) and incubated 10 minutes at 37 C.
  • DMEM + 25 mM HEPES 5 mM theophylline, 10 uM pargyline
  • Wells are treated with forskolin (1 uM final cone) followed immediately by test compound (0.1 and 1 uM for initial screen) and incubated for an additional 10 min at 37 C. Reaction is terminated by removal of the media and addition of 0.5 ml ice cold assay buffer (supplied in RIA kit). Plates are stored at -20 C prior to assessment of cAMP formation by RIA.
  • Ki IC50/((Radioligand conc.)/(l + KD)).
  • SSRI serotonin selective reuptake inhibitor
  • depression including but not limited to major depressive disorder, childhood depression and dysthymia
  • anxiety panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as premenstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction, cognitive deficits resulting from neurodegenerative disorders like Alzheimer's disease, and related illnesses.
  • SSRI serotonin selective reuptake inhibitor
  • some of the compounds of this invention have potent affinity for and antagonist activity at brain 5-HT 1A serotonin receptors.
  • drug mixtures e.g. fluoxetine and pindolol
  • the compounds of this invention are thus interesting and useful for treating depressive illnesses.

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Abstract

L'invention concerne des dérivés de 3-amino chromane et de 2-amino tétraline et sur des compositions contenant ces composés. Ces composés sont utiles pour moduler l'activité d'un récepteur de 5-HT1A (agonisant ou antagonisant) chez un patient. Ces composés sont également utiles pour inhiber la liaison à un récepteur de la sérotonine. L'invention concerne également des procédés d'utilisation des composés de 3-amino chromane et de 2-amino tétraline, et concerne également des compositions contenant ces composés dans le traitement des troubles liés à la sérotonine, tels que la dépression et l'anxiété.
PCT/US2006/023467 2005-06-17 2006-06-15 Composes tricycliques utiles comme inhibiteurs de la serotonine et comme agonistes et antagonistes de 5-ht1a Ceased WO2006138549A1 (fr)

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AU2006259294A AU2006259294A1 (en) 2005-06-17 2006-06-15 Tricyclic compounds useful as serotonin inhibitors and 5-HT1A agonists and antagonists
BRPI0611948-4A BRPI0611948A2 (pt) 2005-06-17 2006-06-15 compostos úteis como inibidores de serotonina e agonistas de antagonista de 5-ht1a
EP06773337A EP1893617A1 (fr) 2005-06-17 2006-06-15 Composes tricycliques utiles comme inhibiteurs de la serotonine et comme agonistes et antagonistes de 5-ht1a
MX2007015772A MX2007015772A (es) 2005-06-17 2006-06-15 Compuestos utiles como inhibidores de serotonina y agonistas y antagonistas de 5-ht-1a.
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8952034B2 (en) 2009-07-27 2015-02-10 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US8962610B2 (en) 2011-07-01 2015-02-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9115096B2 (en) 2011-05-10 2015-08-25 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9193694B2 (en) 2011-07-01 2015-11-24 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US11725010B2 (en) 2019-12-02 2023-08-15 Storm Therapeutics Limited Polyheterocyclic compounds as METTL3 inhibitors

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014209991A1 (fr) * 2013-06-24 2014-12-31 The Johns Hopkins University Procédés pour réduire l'anxiété et l'impulsivité chez des sujets commençant un traitement avec des inhibiteurs de recaptage de sérotonine
WO2016192657A1 (fr) 2015-06-03 2016-12-08 Sunshine Lake Pharma Co., Ltd. Composés de pipérazine substitués, leurs procédés d'utilisation et leurs utilisations
CN106831676A (zh) * 2017-01-20 2017-06-13 烟台舜康生物科技有限公司 一种5‑氰基苯酞的合成方法
WO2020087031A1 (fr) 2018-10-26 2020-04-30 The Research Foundation For The State University Of New York Combinaison d'un inhibiteur de réabsorption spécifique de la sérotonine et d'un agoniste partiel du récepteur de la sérotonine 1a pour réduire la dyskinésie induite par l-dopa

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288748A (en) * 1990-01-11 1994-02-22 The Upjohn Company Centrally acting 6,7,8,9-tetrahydro-3H-benz(e)indole heterocyclics
WO2002088145A1 (fr) * 2001-04-26 2002-11-07 Wyeth Derives azabicyclylmethyle de 7,8-dihydro-1,6,9-trioxa-3-azacyclopenta[a]naphthalene utilises comme antagonistes de as 5-ht¿1a?
WO2002088132A1 (fr) * 2001-04-26 2002-11-07 Wyeth Derives azaheterocyclylmethyle de 2,3-dihydro-1,4-dioxino[2,3-f]quinoline comme antagonistes des 5-ht¿1a?
WO2003010169A1 (fr) * 2001-07-25 2003-02-06 Wyeth Derives azaheterocyclylmethyles de 7,8-dihydro-6h-5-oxa-1-aza-phenanthrene, a effet antidepresseur
WO2004099214A1 (fr) * 2003-04-30 2004-11-18 Wyeth Amino-pyranoquinoleines en tant qu'inhibiteurs de recaptage de la serotonine et agonistes de recepteurs 5-ht1a

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4624954A (en) 1985-12-20 1986-11-25 American Home Products Corporation 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-amines and derivatives thereof, useful for the treatment of cognitive impairments
US4665183A (en) 1985-12-20 1987-05-12 American Home Products Corp. Process for preparing 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-amines and derivatives thereof useful for the treatment of cognitive impairments
US5219857A (en) 1986-10-16 1993-06-15 American Cyanamid Company Method of treating cognitive and related neural behavioral problems
US4904658A (en) 1988-04-15 1990-02-27 American Cyanamid Company Substituted-6H,8H-pyrimido-[1,2,3-cd]purine-8,10-(9H)-diones and substituted-6H,10H-pyrimido[1,2-cd]purin-10-ones
AU645681B2 (en) 1991-05-02 1994-01-20 John Wyeth & Brother Limited Piperazine derivatives
GB9514901D0 (en) 1995-07-20 1995-09-20 American Home Prod Piperazine derivatives
SI0923542T1 (en) 1996-05-31 2004-02-29 Pharmacia & Upjohn Company Aryl substituted cyclic amines as selective dopamine d3 ligands
US6313126B1 (en) 1999-01-07 2001-11-06 American Home Products Corp Arylpiperazinyl-cyclohexyl indole derivatives for the treatment of depression
US6469007B2 (en) 2000-11-28 2002-10-22 Wyeth Serotonergic agents
DE10217006A1 (de) 2002-04-16 2003-11-06 Merck Patent Gmbh Substituierte Indole
UA78999C2 (en) 2002-06-04 2007-05-10 Wyeth Corp 1-(aminoalkyl)-3-sulfonylazaindoles as ligands of 5-hydroxytryptamine-6
TW200401641A (en) 2002-07-18 2004-02-01 Wyeth Corp 1-Heterocyclylalkyl-3-sulfonylindole or-indazole derivatives as 5-hydroxytryptamine-6 ligands
US7153849B2 (en) 2002-09-12 2006-12-26 Wyeth Antidepressant arylpiperazine derivatives of hetrocycle-fused benzodioxans
US20050032873A1 (en) 2003-07-30 2005-02-10 Wyeth 3-Amino chroman and 2-amino tetralin derivatives
DK1648904T3 (da) 2003-07-31 2007-10-22 Wyeth Corp N-sulfonylheterocyclopyrrolalkylaminforbindelser som 5-hydroxytryptamin-6-ligander

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5288748A (en) * 1990-01-11 1994-02-22 The Upjohn Company Centrally acting 6,7,8,9-tetrahydro-3H-benz(e)indole heterocyclics
WO2002088145A1 (fr) * 2001-04-26 2002-11-07 Wyeth Derives azabicyclylmethyle de 7,8-dihydro-1,6,9-trioxa-3-azacyclopenta[a]naphthalene utilises comme antagonistes de as 5-ht¿1a?
WO2002088132A1 (fr) * 2001-04-26 2002-11-07 Wyeth Derives azaheterocyclylmethyle de 2,3-dihydro-1,4-dioxino[2,3-f]quinoline comme antagonistes des 5-ht¿1a?
WO2003010169A1 (fr) * 2001-07-25 2003-02-06 Wyeth Derives azaheterocyclylmethyles de 7,8-dihydro-6h-5-oxa-1-aza-phenanthrene, a effet antidepresseur
WO2004099214A1 (fr) * 2003-04-30 2004-11-18 Wyeth Amino-pyranoquinoleines en tant qu'inhibiteurs de recaptage de la serotonine et agonistes de recepteurs 5-ht1a

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